Negative Responders Research Articles

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study

BackgroundHER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors. Methods84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2+n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2+n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value <0.05, adjusted for multiple testing correction. Results83 biopsies were eligible for analyses following quality control (TRAP cohort n = 40; control cohort n = 43); there were no significant differences in clinical characteristics between the TRAP vs. control the cohort or HER2 positive vs. HER2 negative biopsies. HER2 expression was found to associate with epithelial markers (EPCAM p < 0.001; E-cadherin p < 0.001). Moreover, HER2 expression was associated with a lower expression of immune cell infiltration, such as NK-cells (p < 0.001) and CD8 T-cells (p < 0.001), but also lower expression of immune exhaustion markers (PDCD1LG2, CTLA4; p < 0.001). In non-responders to anti-HER2 treatment, baseline biopsies showed increased expression of immune exhaustion markers, as well as hypoxia and VEGF signalling. DiscussionHER2 expression was associated with epithelial tumor characteristics. The HER2 positive TIME showed reduced immune cell infiltration but also lower expression of inhibitory signals associated with immune exhaustion, questioning the mechanism behind potential clinical benefit of co-administration of anti-HER2 agents and checkpoint inhibitors. As limited response was associated with increased VEGF signalling, studies could investigate potential synergism of targeting VEGF and HER2.

CRT with triple fusion: results of the multicentric, randomized, doble-blinded CRUSTY trial

Abstract Background The possible benefit in terms of cardiac resynchronization therapy (CRT) response using a dynamic automatic algorithm designed to provide triple fusion as compared to conventional optimized biventricular pacing (CBP) is not known. Methods In this randomized, doble blinded, multicentric (13 centers) clinical trial we assigned patients with heart failure, reduced left ventricular ejection fraction and left bundle branch block, who underwent CRT implantation to be optimized using the SyncAV dynamic algorithm or through a conventional method. The primary endpoint was the rate of echocardiographic CRT responders at 6-month follow-up defined as a reduction of the left ventricular end diastolic volume (LVEDV) &amp;gt;15%. Results The study had to be stopped for slow recruitment in the context of the COVID-19 pandemic after enrolling 56 patients; 54 patients were finally analyzed. Patients’ basal characteristics are shown in TABLE. Patients assigned to the SyncAV group presented a narrowest paced QRS (128±16 ms vs. 145±19 ms; p &amp;lt;0.01) and a greater reduction in QRS duration (FIGURE A). Furthermore, more patients in the SyncAV group achieved a paced QRSd &amp;lt;120 mseg (7% vs 35%, p = 0.02). 21 (81%) patients in the SyncAV group and 19 (68%) in the CBP group were classified as CRT responders (OR = 1.99; 95% CI 0.57–7). While patients in the SyncAV group demonstrated a trend towards superior reverse remodeling across all secondary endpoints, statistical significance was not reached (FIGURE B). In the SyncAV group, 2 (8%) patients were categorized as negative responders, and 4 (16%) in the CBP group. A total of 43% of patients improved by at least one category in the NYHA functional classification, while 2 patients experienced worsening, both in the CBP group (clinical negative responders) (FIGURE C). No adverse events directly associated with device programming or the activation of the SyncAV algorithm were reported. Conclusions In this multicenter randomized controlled trial comparing CRT with triple fusion pacing using the SyncAV algorithm to conventional optimized biventricular pacing, there was not reached adequate statistical power to draw a conclusion regarding a potential increase in the CRT response rate. Nevertheless, the use of the SyncAV algorithm resulted in a high proportion of CRT responders. A significant greater reduction of the QRS duration was observed when employing the SyncAV algorithm, leading to a high percentage of cases achieving QRS width normalization. Nonetheless, further investigations are warranted to thoroughly assess the possible clinical benefits associated with triple fusion of LV pacing, RV pacing and intrinsic conduction in HF patients with LBBB.FIGURE

Follow-up of telehealth parent training for sleep disturbances in young children with autism spectrum disorder

Objective/BackgroundBedtime and sleep disturbances are ubiquitous in children with autism. The telehealth delivery of a behavior analytic parent training program was earlier reported to be efficacious in improving child sleep and parent sense of competency. Our aim in this brief report was to determine the durability of the telehealth delivered sleep parent training program (SPT) compared to the control condition in this randomized controlled trial. Telehealth delivery could be a means to expand access to such early treatment if efficacious. Participants/MethodsParents of young children, ages 2–7 years, with autism and co-occurring sleep disturbances were enrolled in this study. Participants were randomized to either SPT or a comparison arm that included non-sleep related parent education except for one session Sleep Parent Education; SPE). Each participant was individually administered a 5 session program delivered over 10 weeks. Outcome measures were collected at weeks 5 and 10 and at post-treatment follow-up at 16 weeks. ResultsFollow-up week 16 data were available for 30 participants randomized to SPT and 24 participants randomized to SPE. Demographics for this follow-up cohort were similar to the full sample. At week 16 follow-up, there was a significant group difference between SPT and SPE the Modified Simonds & Parraga Sleep Questionnaire-Composite Sleep Index (MSPSQ – CSI) (p = 0.011) with an effect size of 0.68. Further, 8 of the 10 children in SPT who were negative responders at the week 10 endpoint were rated as positive responders at week 16 by the treatment masked IE compared to 2 out of 12 in the SPE group (p = 0.008). ConclusionsPost-treatment follow-up data suggests SPT is durable over time compared to SPE, the active control group. Further, for some participants in SPT, a positive responsive emerged after the treatment endpoint. This brief report adds to the efficacy of SPT as a time-limited intervention for insomnia in young autistic children.

Psychiatric risks for worsened mental health after psychedelic use.

Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. A "bottom margin analysis" approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. We find that 16% of the cohort falls into the "negative responder" subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality disorder subsample (b = 1.425, p < 0.05). We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.

A cross-sectional survey on the effects of ambient temperature and humidity on health outcomes in individuals with chronic respiratory disease.

Extremes of temperature and humidity are associated with adverse respiratory symptoms, reduced lung function, and increased exacerbations among individuals living with chronic obstructive pulmonary disease (COPD). To describe the reported effects of temperature and humidity extremes on the health outcomes, health status and physical activity (PA) in individuals living with COPD. A cross-sectional self-reported survey collected the effects on health status (COPD Assessment Test [CAT]), PA, and health outcomes in 1) moderate/ideal (14 to 21°C, 30 to 50% relative humidity [RH]), 2) hot and humid (≥ 25°C, > 50% RH) and 3) cold and dry (≤ 5°C, < 30% RH) weather conditions. Participants were ≥ 40 years old with COPD or related chronic respiratory diseases (e.g., asthma, sleep apnea, interstitial lung disease, lung cancer) and residing in Canada for ≥ 1 year. Negative responders to weather extremes were a priori defined as having a change of ≥ 2 points in the CAT. Thirty-six participants responded; the mean age (SD) was 65 (11) years, and 23 (64%) were females. Compared to ideal conditions, 23 (66%) and 24 (69%) were negatively affected by cold/dry and hot/humid weather, respectively. Health status was significantly lower, and PA amount and difficulty level were reduced in hot/humid and cold/dry conditions compared with ideal conditions. The number of exacerbations in hot/humid was significantly higher compared to ideal conditions. More participants were negatively affected by extremes of weather: health status worsened, PA decreased, and frequency of exacerbations was higher compared to ideal. Future prospective studies should directly and objectively investigate different combinations of extreme temperature and humidity levels on symptoms and PA to understand their long-term health outcomes.

Diagnosis and Prognosis in Disorders of Consciousness: An Active Paradigm fMRI Study

Diagnoses in patients with disorders of consciousness are prone to misdiagnosis; thus, research has sought approaches to increase reliability, for instance, with functional MRI. By applying a motor imagery task, patients showing covert command following despite the absence of behavioural signs of awareness can be identified as being in a cognitive motor dissociation. This study seeks to determine the proportion of patients, with unresponsive wakefulness syndrome and minimally conscious state, who display covert command following. Moreover, the prognostic value of the improved diagnosis and different methodical approaches to analyse the functional MRI data were evaluated. 73 disorder of consciousness patients (35 unresponsive, 35 minimally conscious, and three already recovered) underwent weekly standardized behavioural assessments with the coma-recovery scale—revised and one functional MRI examination comparing their brain activations in the supplementary motor area between phases of imaging playing tennis and rest. 27 healthy controls served as a control group. The data was evaluated using different region-of-interest analyses (one- and two-tailed small-volume correction and region-of-interest exploration approaches) and a whole-brain analysis. Based on the one-tailed small volume correction data, seven patients, all of nontraumatic aetiology, showed covert command following. The one-tailed region-of-interest exploration identified three additional responders. 10 patients showed significantly more activation during rest than during the imagery paradigm (negative responders). 40% of patients (minimally conscious patients being three times more likely) showed significant activations in the whole brain analysis. Besides, no significant further associations were found between covert command following and clinical parameters. The analyses showed that the tennis paradigm could identify patients with cognitive motor dissociation with a nontraumatic aetiology, but our data failed to show any short-term prognostic validity. The relevance of negative responders and activated regions outside of the region of interest should be further investigated.

Marine toxin domoic acid alters protistan community structure and assembly process in sediments

Domoic acid (DA)-producing algal blooms have been the issue of worldwide concerns in recent decades, but there has never been any attempt to investigate the effects of DA on microbial ecology in marine environments. Protists are considered to be key regulators of microbial activity, community structure and evolution, we therefore explore the effect of DA on the ecology of protists via metagenome in this work. The results indicate that trace amounts of DA can act as a stressor to alter alpha and beta diversity of protistan community. Among trophic functional groups, consumers and phototrophs are negative responders of DA, implying DA is potentially capable of functional-level effects in the ocean. Moreover, microecological theory reveals that induction of DA increases the role of deterministic processes in microbial community assembly, thus altering the biotic relationships and successional processes in symbiotic patterns. Finally, we demonstrate that the mechanism by which DA shapes protistan ecological network is by acting on phototrophs, which triggers cascading effects in networks and eventually leading to shifts in ecological succession of protists. Overall, our results present the first perspective regarding the effects of DA on marine microbial ecology, which will supplement timely information on the ecological impacts of DA in the ocean.

BNT162b2 Third Booster Dose Significantly Increases the Humoral Response Assessed by Both RBD IgG and Neutralizing Antibodies in Renal Transplant Recipients.

Background: An impaired humoral response to full dose of BNT162b2 vaccine was observed in renal transplant recipients (RTR). Methods: To reveal predictors for humoral response to third vaccine, patients were stratified to positive (N = 85) and negative (N = 14) response groups based on receptor-binding domain (RBD) IgG ≥1.1 and neutralizing antibodies (NA) ≥ 16 dilution versus RBD IgG <1.1 or NA < 16, respectively. NA were detected using a SARS-CoV-2 pseudo-virus. Results: Response rate increased from 32.3% (32/99) before the third dose to 85.9% (85/99) post-third vaccine with a significant rise in geometric mean titers (GMTs) for RBD IgG and NA [0.79 (95% CI 0.65–0.96) vs. 3.08 (95% CI 2.76–3.45), p < 0.001 and 17.46 (95% CI 12.38–24.62) vs. 362.2 (95% CI 220.7–594.6), p < 0.001 respective. 80.6% (54/67) seroconverted and 96.9% (31/32) remained positive following the vaccine with a significant increase in GMTs for RBD IgG and NA. Age, ESRD secondary to diabetic nephropathy (DN) and renal allograft function were independent predictors for antibody response in RTR. Mycophenolic acid (MPA) use and dose had no impact on humoral response following the third booster. AEs were recorded for 70.1% of RTR population. Systemic AEs were more common in recipients with a positive humoral response as opposed to non-responders (45.2% versus 15.4% respectively, p = 0.04). Conclusion: 85.9% of RTR develop NA to BNT162b2 third vaccine, found effective in both negative and positive responders prior to the vaccine. Antigenic re-exposure overcame the suppressive effect of MPA on antibody response in RTR.

An Analysis of Serological Response and Infection Outcomes Following Oxford-AstraZeneca (AZD1222) and Pfizer-BioNTech (mRNA BNT162b2) SARS-CoV-2 Vaccines in Kidney and Kidney-pancreas Transplants.

Background.Severe acute respiratory syndrome coronavirus 2 is associated with high mortality among transplant recipients. Comparative data that define humoral responses to the Oxford-AstraZeneca (AZ) and BNT162b2 (Pfizer-BioNTech) vaccines are limited.Methods.We recruited 920 kidney transplant patients receiving at least 1 dose of severe acute respiratory syndrome coronavirus 2 vaccine, excluding patients with virus pre-exposure. Serological status was determined with the COVID-SeroKlir ELISA (Kantaro-EKF Diagnostics). Patients with a corrected antibody level of <0.7 AU/mL were considered seronegative.Results.Four hundred ninety-five AZ and 141 Pfizer patients had a sample analyzed after first dose and 593 after second dose (346 AZ versus 247 Pfizer). After first dose, 25.7% of patients seroconverted (26.6% AZ, 22.8% Pfizer). After second dose, 148 (42.8%) of AZ seroconverted compared with 130 (52.6%) of Pfizer (P = 0.02; hazard ratio, 1.48; 95% confidence interval, 1.07-2.06). When negative responders were excluded, Pfizer patients were shown to have significantly higher response than AZ patients (median 2.6 versus 1.78 AU/mL, P = 0.005).Patients on mycophenolate had a reduced seroconversion rate (42.2% versus 61.4%; P < 0.001; hazard ratio, 2.17) and reduced antibody levels (0.47 versus 1.22 AU/mL, P = 0.001), and this effect was dose dependent (P = 0.05). Prednisolone reduced the seroconversion from 58.2% to 43.6% (P = 0.03) among Pfizer but not AZ recipients. Regression analysis showed that antibody levels were reduced by older age (P = 0.002), mycophenolate (P < 0.001), AZ vaccine (versus Pfizer, P = 0.001), and male gender (P = 0.02). Sixteen of 17 serious postvaccine infections occurred to patients who did not seroconvert.Conclusions.Both seroconversion and antibody levels are lower in AZ compared with Pfizer vaccinated recipients following 2 vaccine doses. Mycophenolate was associated with lower antibody responses in a dose-dependent manner. Serious postvaccine infections occurred among seronegative recipients.

Characterization of the TCR β Chain Repertoire in Peripheral Blood from Hepatitis B Vaccine Responders and Non-Responders.

BackgroundHepatitis B (HepB) vaccination can effectively prevent the prevalence of hepatitis B virus (HBV) infection. However, the incidence of vaccination failure is about 5~10% and the underlying molecular mechanisms are poorly understood. T cells have an essential role in the recipient’s immune response to vaccine, which could be elucidated by high-throughput sequencing (HTS) and bioinformatics analysis.MethodsWe conducted HTS of the T cell receptor β chain (TRB) complementarity-determining region 3 (CDR3) repertoires in eighteen positive responders (responders) and 10 negative responders (non-responders) who all had HepB vaccination, the repertoire features of BV, BJ and V-J genes and their diversity, respectively, were compared between the positive and negative responders using the Mann–Whitney test. Moreover, the relatively conserved motifs in CDR3 were revealed and compared to those in the other group’s report.ResultsThe diversity of TRB CDR3 and the frequencies of BV27 and BV7-9 are significantly increased for HepB vaccine responders compared to those in non-responders. The motifs of CDR3s in BV27/J1-1, BV27/J2-5, and BV7-9/J2-5, respectively, were most expressed as “NTE”, “QETQ”, and “GG-Q (E)-ETQ”. Moreover, the motif “KLNSPL” was determined in nearly 80% CDR3s in BV27/J1-6 from HepB vaccine responders for the first time.ConclusionOur results present the comprehensive profiles of TRB CDR3 in the HepB vaccine responders and non-responders after standard vaccination protocol and determine the relatively conservative motifs of CDR3s that may respond to the HepB vaccine. Further results suggest that the profile of TRB repertoire could distinguish the HepB vaccine responders from non-responders and provide a new target for optimizing and improving the efficiency of the HepB vaccine.

Profiling T cell receptor β-chain in responders after immunization with recombinant hepatitis B vaccine.

T cells with edited T cell receptor β-chain variable (TRBV) are involved in the immune response to recombinant hepatitis B surface antigen (rHBsAg) vaccine and the production of hepatitis B surface antibody (HBsAb). The immune repertoire (IR) profile and mechanism of vaccination positive responders (VPR) with rHBsAg are not fully understood. The IR of six VPRs (HBsAb+, HbsAg-) with rHBsAg vaccination was established by the high throughput sequencing technique and bioinformatics analysis and compared with those in five vaccination negative responders (VNRs) (HbsAb-, HbsAg-) who were also inoculated with rHBsAg. The repertoire features of the BV, BJ and V (CDR3)J genes and immune diversity in peripheral blood mononuclear cells, respectively, were analyzed for each subject. There was no significant difference in sequencing amplification indices of each sample. However, TRBV15/BJ2-3 demonstrated significantly high expression levels in VPR compared to those in the VNR group (both p < 0.05). Further results showed that the BV15/BJ2-5 level was significantly increased for VPR compared to that of VNR group. Interestingly, the motif of CDR3 in TRBV15/BJ2-5 was mostly expressed as "GGETQ" or "GETQ". Additionally, there was no remarkable difference between the two groups of distribution with respect to the different clone expression levels of V (CDR3)J. The features of IR in the VPR and VNR will contribute to the exploration of the mechanism of the positive response to rHBsAg, and also contribute to development of optimized hepatitis B vaccine, in addition to providing a partial interpretation of the VNR who has a relatively low infection with HBV.

Keystone taxa-mediated bacteriome response shapes the resilience of the paddy ecosystem to fungicide triadimefon contamination

The increasing input of fungicides has emerged as a global concern for agroecosystem stability and sustainability. Agroecosystem resilience has been linked to microbiome response, however, is not well understood. Focusing on a widespread triazole-class fungicide triadimefon in the paddy ecosystem, we characterized that the soils and sediments were dominant triadimefon reservoirs with the peak level at 195 μg kg−1 and 31.3 μg kg−1, respectively, but essential for the resilience of paddy ecosystem to triadimefon. In paddy simulation models, the half-life of triadimefon in soil-sediment was 8.4–28.9 days, while it was prolonged to 86.6–115.5 days after elimination of resident microbial community. Phospholipid fatty acid profiling and high-throughput sequencing showed that the distinctive bacterial community responses contributed to variable degradation of triadimefon in paddy soils and sediments. Sphingomonas and Xanthomonas were identified as positive responders of the keystone taxa in the responsive bacteriome, whereas Enterobacter were negative responders that declined over time. Synthetic assemblages combined with quantitative polymerase chain reaction further validated that Sphingomonas and Xanthomonas were involved in sustaining soil-sediment resilience to triadimefon contamination. Collectively, our results revealed that the shaping of soil and sediment bacteriomes was responsible for the resilience of the paddy agroecosystem to fungicide contamination.

Explaining heterogeneity of individual treatment causal effects by subgroup discovery: An observational case study in antibiotics treatment of acute rhino-sinusitis

ObjectivesIndividuals may respond differently to the same treatment, and there is a need to understand such heterogeneity of causal individual treatment effects. We propose and evaluate a modelling approach to better understand this heterogeneity from observational studies by identifying patient subgroups with a markedly deviating response to treatment. We illustrate this approach in a primary care case-study of antibiotic (AB) prescription on recovery from acute rhino-sinusitis (ARS). MethodsOur approach consists of four stages and is applied to a large dataset in primary care dataset of 24,392 patients suspected of suffering from ARS. We first identify pre-treatment variables that either confound the relationship between treatment and outcome or are risk factors of the outcome. Second, based on the pre-treatment variables we create Synthetic Random Forest (SRF) models to compute the potential outcomes and subsequently the causal individual treatment effect (ITE) estimates. Third, we perform subgroup discovery using the ITE estimates as outcomes to identify positive and negative responders. Fourth, we evaluate the predictive performance of the identified subgroups for predicting the outcome in two ways: the likelihood ratio test, and whether the subgroups are selected via the Akaike Information Criterion (AIC) using backward stepwise variable selection. We validate the whole modelling strategy by means of 10-fold-cross-validation. ResultsBased on 20 pre-treatment variables, four subgroups (three for positive responders and one for negative responders) were identified. The log likelihood ratio tests showed that the subgroups were significant. Variable selection using the AIC kept two of the four subgroups, one for positive responders and one for negative responders. As for the validation of the whole modelling strategy, all reported measures (the number of pre-treatment variables associated with the outcome, number of subgroups, number of subgroups surviving variable selection and coverage) showed little variation. ConclusionsWith the proposed approach, we identified subgroups of positive and negative responders to treatment that markedly deviate from the mean response. The subgroups showed additive predictive value of the outcome. The modelling approach strategy was shown to be robust on this dataset. Our approach was thus able to discover understandable subgroups from observational data that have predictive value and which may be considered by the clinical users to get insight into who responds positively or negatively to a proposed treatment.

Effects of a 16-Week Multimodal Exercise Program on Physical Performance in Individuals With Dementia: A Multicenter Randomized Controlled Trial.

Dementia affects physical as well as cognitive performance. In individuals with dementia (IWD), decline in physical performance increases with disease progression and is associated with higher functional dependence and decreased quality of life. It is paramount to examine factors that potentially preserve physical performance in IWD, particularly in light of conflicting findings on the effectiveness of physical activity interventions on physical performance of IWD, mainly due to limited number of high-quality studies, large heterogeneity in methods used, or insufficient reporting of methods. The aim of this study was to investigate the effects of a 16-week multimodal exercise program (MEP) combining physical and cognitive tasks on physical performance in IWD, and to identify individual characteristics of MEP responders. A multicenter randomized controlled trial with assessment methods identified by an expert panel was conducted. We included 319 IWD of mild to moderate severity, older than 65 years, who underwent a standardized MEP specifically designed for IWD. At baseline and immediately after the MEP, we assessed physical performance (ie, mobility, balance, and strength) and function of lower extremities (primary outcomes). Potential effects of the MEP on physical performance were identified using 2-factor analyses of variance with repeated measurements within 2 samples (ie, intention-to-treat and per-protocol sample). Additionally, we compared characteristics related to physical performance between positive, non-, and negative responders. Neither analysis procedure revealed statistically significant time×group effects. However, 28% to 40% of participants were positive responders with regard to balance, and strength and function of lower extremities; and these persons had statistically significant lower baseline performance in the corresponding assessments. This randomized controlled trial revealed no overall effects of the MEP on physical performance, probably due to high heterogeneity of the study sample. Findings in responder analysis showed that IWD with lower physical performance at baseline tended to benefit more than those with higher baseline performance. Thus, a higher degree of individualization of the MEP depending on baseline performance on IWD may improve overall MEP effectiveness.

Intra-individual physiological response of recreational runners to different training mesocycles: a randomized cross-over study

PurposePronounced differences in individual physiological adaptation may occur following various training mesocycles in runners. Here we aimed to assess the individual changes in performance and physiological adaptation of recreational runners performing mesocycles with different intensity, duration and frequency.MethodsEmploying a randomized cross-over design, the intra-individual physiological responses [i.e., peak ({dot{text V}}{text O}_{2 {rm peak}}) and submaximal ({dot{text V}}{text O}_{2 {rm submax}}) oxygen uptake, velocity at lactate thresholds (V2, V4)] and performance (time-to-exhaustion (TTE)) of 13 recreational runners who performed three 3-week sessions of high-intensity interval training (HIIT), high-volume low-intensity training (HVLIT) or more but shorter sessions of HVLIT (high-frequency training; HFT) were assessed.Results{dot{text V}}{text O}_{2 {rm submax}}, V2, V4 and TTE were not altered by HIIT, HVLIT or HFT (p > 0.05). {dot{text V}}{text O}_{2 {rm peak}} improved to the same extent following HVLIT (p = 0.045) and HFT (p = 0.02). The number of moderately negative responders was higher following HIIT (15.4%); and HFT (15.4%) than HVLIT (7.6%). The number of very positive responders was higher following HVLIT (38.5%) than HFT (23%) or HIIT (7.7%). 46% of the runners responded positively to two mesocycles, while 23% did not respond to any.ConclusionOn a group level, none of the interventions altered {dot{text V}}{text O}_{2 {rm submax}}, V2, V4 or TTE, while HVLIT and HFT improved {dot{text V}}{text O}_{2 {rm peak}}. The mean adaptation index indicated similar numbers of positive, negative and non-responders to HIIT, HVLIT and HFT, but more very positive responders to HVLIT than HFT or HIIT. 46% responded positively to two mesocycles, while 23% did not respond to any. These findings indicate that the magnitude of responses to HIIT, HVLIT and HFT is highly individual and no pattern was apparent.

Bacterial communities in the plant phyllosphere harbour distinct responders to a broad-spectrum pesticide

Pesticide application can be accompanied by harmful non-target effects that affect humans, animals, as well as whole ecosystems. However, such effects remain mainly unaddressed in connection with microorganisms, and especially bacteria therein, which are essential for ecosystem functioning and host health. We analysed bacterial communities by sequencing 16S rRNA gene fragment amplicons following spray application of a broad-spectrum fungicide based on the active ingredient N-(3,5-dichlorophenyl) succinimide on Nicotiana tabacum L. leaves. The plant's phyllosphere was predominantly colonized by Proteobacteria, with Alphaproteobacteria accounting for up to 33.8% of the indigenous bacterial community. Bioinformatic analyses indicated that pesticide applications had an effect on the core microbiome as well as the rare microbiome. Moreover, the interference of the pesticide with phyllosphere bacteria was found to be selective. We have identified four positive responders including an ASV assigned to the genus Acinetobacter and 12 negative responders mainly assigned to bacterial genera known for beneficial plant-microbe interactions, including Stenotrophomonas, Sphingomonas, Flavobacterium and Serratia. Complementary inference of bacterial functioning on community level indicated that microbes with distinct stress response systems were likely enriched in the conducted treatments. The overall findings confirmed that pesticide treatments can induce measureable shifts in non-target bacterial communities colonizing the plant phyllosphere. They also indicate that potentially beneficial bacteria, which are known for their intrinsic association with plants, are among the most sensitive responders to the employed fungicide and thus highlight the importance of off-target studies in the context of the plant microbiome.

A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept.

Background and aims In recent years, focus on assessing descending pain modulation or conditioning pain modulation (CPM) has emerged in patients with chronic pain. This requires reliable and simple to use bed-side tools to be applied in the clinic. The aim of the present pilot study was to develop and provide proof-of-concept of a simple clinically applicable bed-side tool for assessing CPM. Methods A group of 26 healthy volunteers participated in the experiment. Pressure pain thresholds (PPT) were assessed as test stimuli from the lower leg before, during and 5min after delivering the conditioning tonic painful pressure stimulation. The tonic stimulus was delivered for 2min by a custom-made spring-loaded finger pressure device applying a fixed pressure (2.2kg) to the index finger nail. The pain intensity provoked by the tonic stimulus was continuously recorded on a 0-10cm Visual Analog Scale (VAS). Results The median tonic pain stimulus intensity was 6.7cm (interquartile range: 4.6-8.4cm) on the 10cm VAS. The mean PPT increased significantly (P=0.034) by 55±126kPa from 518±173kPa before to 573±228kPa during conditioning stimulation. When analyzing the individual CPM responses (increases in PPT), a distribution of positive and negative CPM responders was observed with 69% of the individuals classified as positive CPM responders (increased PPTs=anti-nociceptive) and the rest as negative CPM responders (no or decreased PPTs=Pro-nociceptive). This particular responder distribution explains the large variation in the averaged CPM responses observed in many CPM studies. The strongest positive CPM response was an increase of 418kPa and the strongest negative CPM response was a decrease of 140kPa. Conclusions The present newly developed conditioning pain stimulator provides a simple, applicable tool for routine CPM assessment in clinical practice. Further, reporting averaged CPM effects should be replaced by categorizing volunteers/patients into anti-nociceptive and pro-nociceptive CPM groups. Implications The finger pressure device provided moderate-to-high pain intensities and was useful for inducing conditioning stimuli. Therefore, the finger pressure device could be a useful bed-side method for measuring CPM in clinical settings with limited time available. Future bed-side studies involving patient populations are warranted to determine the usefulness of the method.

Effects of a 16-week multimodal exercise program on gait performance in individuals with dementia: a multicenter randomized controlled trial

BackgroundThere is a high prevalence of gait impairments in individuals with dementia (IWD). Gait impairments are associated with increased risk of falls, disability, and economic burden for health care systems. Only few studies have investigated the effectiveness of physical activity on gait performance in IWD, reporting promising but inconsistent results. Thus, this study aimed to investigate the effectiveness of a multimodal exercise program (MEP) on gait performance in IWD.MethodsIn this parallel-group randomized controlled trial, we enrolled 319 IWD of mild to moderate severity, living in care facilities, aged ≥ 65 years, and being able to walk at least 10 m. The control group (n = 118) received conventional treatment, whereas the intervention group (n = 201) additionally participated in a 16-week MEP specifically tailored to IWD. We examined the effects of the MEP on spatiotemporal gait parameters and dual task costs by using the gait analysis system GAITRite. Additionally, we compared characteristics between positive, non-, and negative responders, and investigated the impact of changes in underlying motor and cognitive performance in the intervention group by conducting multiple regression analyses.ResultsTwo-factor analyses of variance with repeated measurements did not reveal any statistically significant time*group effects on either spatiotemporal gait parameters or dual task costs. Differences in baseline gait performance, mobility, lower limb strength, and severity of cognitive impairments were observed between positive, non-, and negative responders. Positive responders were characterized by lower motor performance compared to negative and non-responders, while non-responders showed better cognitive performance than negative responders. Changes in lower limb strength and function, mobility, executive function, attention, and working memory explained up to 39.4% of the variance of changes in gait performance.ConclusionsThe effectiveness of a standardized MEP on gait performance in IWD was limited, probably due to insufficient intensity and amount of specific walking tasks as well as the large heterogeneity of the sample. However, additional analyses revealed prerequisites of individual characteristics and impacts of changes in underlying motor and cognitive performance. Considering such factors may improve the effectiveness of a physical activity intervention among IWD.Trial registrationDRKS00010538 (German Clinical Trial Register, date of registration: 01 June 2016, retrospectively registered, https://www.drks.de/drks_web/setLocale_EN.do).

Reproducibility Of The Impact Of Menstrual Phase On Arterial Stiffness Over Two Consecutive Menstrual Cycles

Chronic increases in arterial stiffness are associated with increased risk of cardiovascular disease. Estrogen (E2), the primary female sex hormone, has been found to have cardioprotective effects, with several but not all, studies reporting a reduction in arterial stiffness in the late follicular (high E2; LF) phase compared to the early follicular (low E2; EF) phase of the menstrual cycle. Individual heterogeneity in the impact of phase on arterial stiffness and the consistency of these responses across consecutive cycles has yet to be explored. PURPOSE: to determine the impact of menstrual phase E2 fluctuations on arterial stiffness over two consecutive cycles. METHODS: 13 premenopausal women completed 4 experimental visits over 2 menstrual cycles (EFvisit 1, LFvisit 2, EFvisit 3, LFvisit 4). Central (CF) and peripheral (FF) PWV were measured twice during each visit using arterial tonometry. Participants were classified as positive, negative or non-responders, wherein positive responders experienced a reduction in PWV from EF to LF and negative responders experienced an increase in PWV from EF to LF that was greater than 2*typical error. RESULTS: At the group level, CF PWV did not differ between phases (p=0.11) or cycles (p=0.18; EFvisit 1=5.8±0.8, LFvisit 2=5.6±0.5, EFvisit 3=5.9±0.6, LFvisit 4=5.8±0.7). Likewise, FF PWV did not differ between phases (p=0.979) or cycles (p=0.58; EFvisit 1=8.1±1.0, LFvisit 2=8.1±1.1, EFvisit 3=7.9±1.4, LFvisit 4=8.0±1.3). Phase changes in E2 were not associated with phase changes in PWV in cycle 1 (CF: r=0.38, p=0.20; FF: r=0.11, p=0.73) or cycle 2 (FF: r=0.38, p=0.36). Classification of individuals as responders or non-responders revealed that no participants were consistently positive or negative responders for both cycles. CONCLUSION: At the group level, arterial stiffness was not impacted by menstrual phase over two cycles. Individual changes in arterial stiffness were inconsistent, with phase changes in cycle 1 not reflecting phase changes in cycle 2. Variability in phase changes in arterial stiffness does not appear to be driven by inter-individual differences in E2 fluctuation across phase. Future research is needed to investigate the mechanisms resulting in inter-individual variability in arterial stiffness and inconsistency between cycles. Funded by NSERC

Physical deterioration and adaptive recovery in physically inactive breast cancer patients during adjuvant chemotherapy: a randomised controlled trial

Cardiorespiratory fitness is an independent risk factor for cardiovascular disease and shortened life expectancy in breast cancer survivors. This randomised controlled trial (n = 153) was designed for patients with a physically inactive lifestyle prediagnosis and concurrently referred to adjuvant chemotherapy. We compared two 12-week exercise interventions aimed at physiological and patient-reported outcomes (cardiorespiratory fitness, muscle strength, metabolic markers, physical activity, pain, fatigue), including a 39-week follow-up. A supervised hospital-based moderate to high intensity group exercise intervention was compared to an instructed home-based individual pedometer intervention. The two 12-week interventions included oncologists’ recommendations and systematic health counselling. Outcomes were measured at baseline and week 6, 12 and 39. Primary outcome cardiorespiratory fitness declined significantly during chemotherapy and was restored in both interventions at follow-up. The interventions effectively engaged breast cancer patients in sustaining physical activities during and following adjuvant treatment. A composite metabolic score improved significantly. Positive cardiorespiratory fitness responders had improved clinical effects on fatigue, pain and dyspnoea versus negative responders. We conclude that a loss of cardiorespiratory fitness among physically inactive breast cancer patients may be restored by early initiated interventions and by adapting to physical activity recommendations, leading to a decreased cardiovascular risk profile in breast cancer survivors.